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Elevated Seminal Plasma Estradiol and Epigenetic Inactivation of ESR1 and ESR2 Is Associated with CP/CPPS

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Elevated Seminal Plasma Estradiol and Epigenetic Inactivation of ESR1 and ESR2 Is Associated with CP/CPPS www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 28), pp: 19623-19639 Research Paper Elevated seminal plasma estradiol and epigenetic inactivation of ESR1 and ESR2 is associated with CP/CPPS Nils Nesheim1,2, Stuart Ellem3,4, Temuujin Dansranjavin1, Christina Hagenkötter1,2, Elena Berg1,2, Rupert Schambeck1,2, Hans-Christian Schuppe1, Adrian Pilatz1, Gail Risbridger3, Wolfgang Weidner1, Florian Wagenlehner1,* and Undraga Schagdarsurengin1,2,* 1Clinic of Urology, Pediatric Urology and Andrology, Justus Liebig University, Giessen, Germany 2Working Group Epigenetics of the Urogenital System, Clinic of Urology, Pediatric Urology and Andrology, Justus Liebig University, Giessen, Germany 3Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia 4Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia *These authors contributed equally Correspondence to: Undraga Schagdarsurengin, email: [email protected] Florian Wagenlehner, email: [email protected] Keywords: chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); liquid biopsies; estradiol; estrogene receptor; epigenetic inactivation Received: October 05, 2017 Accepted: February 24, 2018 Published: April 13, 2018 Copyright: Nesheim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is associated with urinary tract symptoms and hormonal imbalances amongst others. The heterogeneous clinical presentation, unexplored molecular background and lack of prostate biopsies complicate therapy. Here, using liquid biopsies, we performed a comprehensive translational study on men diagnosed with CP/CPPS type III (n = 50; median age 39.8, range 23–65) and age-matched controls (n = 61; median age 36.8, range 20–69), considering biochemical parameters of blood and ejaculates, and epigenetic regulation of the estrogen receptor genes (ESR1 and ESR2) in leukocytes isolated from blood (systemic regulation) and in somatic cells isolated from ejaculates (local regulation). We found elevated 17β-estradiol (E2) levels in seminal plasma, but not in blood plasma, that was significantly associated with CP/ CPPS and impaired urinary tract symptoms. In ejaculated somatic cells of CP/CPPS patients we found that ESR1 and ESR2 were both significantly higher methylated in CpG-promoters and expressionally down-regulated in comparison to controls. Mast cells are reported to contribute to CP/CPPS and are estrogen responsive. Consistent with this, we found that E2 –treatment of human mast cell lines (HMC-1 and LAD2) resulted in altered cytokine and chemokine expression. Interestingly, in HMC-1 cells, possessing epigenetically inactivated ESR1 and ESR2, E2 –treatment led to a reduced transcription of a number of inflammatory genes. Overall, these data suggest that elevated local E2 levels associate with an epigenetic down-regulation of the estrogen receptors and have a prominent role in CP/CPPS. Investigating E2 levels in semen could therefore serve as a promising biomarker to select patients for estrogen targeted therapy. www.oncotarget.com 19623 Oncotarget INTRODUCTION of multiple animal models such as experimental autoimmune prostatitis (EAP). These include mouse The prostate is particularly susceptible to disease, models of chronic prostatic inflammation induced by with ~90% of men developing histological benign immunization with prostate antigen (PAg) [13], rat prostatic hyperplasia (BPH) by the age of 80 [1], ~11.6% models with chronic inflammation induced by combined of all men developing prostate cancer (PCa) during testosterone and E2 treatment [14], or a transgenic mouse their lifetime [2], and up to 16% developing chronic model with aromatase (ARO+) over-expression leading prostatitis/chronic pelvic pain syndrome (CP/CPPS) [3]. to chronic prostatitis and prostate pre-malignancy with CP/CPPS generally receives less attention and remains increased mast cell infiltration [15]. Further studies have poorly understood, even though it has a high disease subsequently linked mast cell infiltration and prostatic burden. CP/CPPS is characterized by pelvic pain, ongoing estrogen dominance to prostate cancer [16]. Elevated urinary tract symptoms without detectable pathogens tryptase levels were also present in the expressed prostatic or identifiable aetiology, and various other signs and secretions (EPS) of CP/CPPS patients [17], underscoring symptoms, assigning the syndrome to the class of chronic the clinical significance of mast cells and drawing inflammatory and perhaps autoimmune disorders [4]. attention to estrogen as a potential mediator of both PCa There is currently no reliable biomarker for CP/ and CP/CPPS. CPPS. Instead, classification as inflammatory (IIIa: At least two compounds targeting estrogen signaling leukocytes) or non-inflammatory (IIIb: no leukocytes) is have been studied for treatment of CP/CPPS. Patients were based on upon the presence or absence of leukocytes in shown to profit by treatment of Mepartricin, an estrogen expressed prostatic secretions or post prostatic massage reabsorption inhibitor [18], but also from quercetin, a urine [5]. However, this classification does not have plant isoflavonoid with anti-estrogenic properties and a implications for differential treatment [6], nor does the ~9 fold higher affinity to estrogen receptor beta (ERβ, presence of leukocytes in prostatic secretions correlate ESR2 gene) than to ER-alpha (ERα, ESR1 gene) [19–21]. with severity of symptoms [7]. Instead, it was the It is interesting to note that ERβ is a potent suppressor introduction of a multimodal treatment system (UPOINT) of inflammation in multiple tissues/organs, including the with symptom-specific patient stratification that has led brain and bowel [22, 23]. Hence, an aberrant and increased to significant advances in disease management [8, 9], prostatic ERα:ERβ ratio may contribute to CP/CPPS. indicating that multiple disease entities could be concealed Administration of the histone deactelyase (HDAC) behind the diagnosis CP/CPPS. Nevertheless, the lack inhibitor MS-275 led to EAP attenuation in a rat model of reliable biomarkers and well-established patho- [24], highlighting the epigenetic dimensions of the mechanisms are the reasons why the syndrome is treated inflammatory response as a possible target for epigenetic in a phenotype-directed manner. The high prevalence and drugs. Our group recently reported epigenetic inactivation morbidity of CP/CPPS, as well as the possible link to PCa of CXCR4 (C-X-C motif receptor of the chemokine and/or BPH upon aging, stresses the need for a deeper understanding of the underlying mechanisms. CXCL12/SDF1) in CP/CPPS patients’ liquid biopsies Steroid sex hormones, particularly testosterone [25], showing that CP/CPPS is accompanied by systemic and organ-specific epigenetic changes. Here, we extend and estradiol (E2), play key roles in the development and maintenance of the reproductive systems. The synthesis upon this and examine in a prospective analytical of estrogens from androgens is catalyzed by aromatase. comparative study whether epigenetic aberrations of Estrogen action in the male is viewed in at least two the sex hormone receptor genes ESR1, ESR2 and AR different ways: systemic endocrine effects acting through (androgen receptor) occur in CP/CPPS and associate with the pituitary gland to indirectly lower androgens and local the clinical phenotype. This study was approved by the effects that directly target prostate tissue by estrogen Ethics Commission of the Medical Faculty of the Justus- receptors [10]. Androgen and estrogen signaling plays Liebig-University Giessen (ethical votes, AZ.: 55/13; a significant role in normal and abnormal growth of AZ.: 123/12) and all subjects provided written informed the prostate gland [10]. Studies examining the steroid consent. To provide mechanistic insights for our findings hormones in CP/CPPS, however, are equivocal, reporting in patients’ liquid biopsies, and to explore the role of mast either elevated systemic testosterone and unchanged cells and estrogen in CP/CPPS, we studied human mast estradiol levels [11], or elevated systemic estradiol levels, cells and the influence of estrogen on their inflammatory but unchanged testosterone levels [12]. In the latter, it profile. Overall, we provide new molecular insights into is interesting to note that this patient cohort also had an the chronification of prostatitis and demonstrate that elevated body mass index, so adipose aromatase activity seminal plasma estradiol levels and epigenetic state of could account for the elevated systemic estradiol levels. estrogen receptor genes, respectively, may be a novel Prostate biopsies in patients with CP/CPPS are not diagnostic tool for CP/CPPS patients that could be used to routinely performed, which has led to the development select patients for targeted therapy. www.oncotarget.com 19624 Oncotarget RESULTS between blood testosterone and E2 in seminal plasma was found (R2 = 0.2953, p = 0.0363; Figure 1C.3). Increased concentration of 17β-estradiol in seminal plasma is associated with CP/CPPS and Semen samples are a source of inflammatory impaired urogenital tract symptoms markers of CP/CPPS Whole
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